A 38 residue synthetic peptide fragment of the transmembrane glycoprotein (gp4l) of HIV-1 is a powerful inhibitor of in vitro replication in several laboratory and primary viral isolates. This peptide (DP-107) is an obvious candidate for an urgently needed antiviral drug. However, difficulties in delivery and rapid clearing make peptides notoriously poor drugs. The alternative is a non-peptide drug that mimics the structure and function of DP-107. This proposal describes detailed multidimensional nuclear magnetic resonance (NMR) studies aimed at determining the structure of DP-107 under physiological conditions. The resulting structure will be a critical first step in the design of a drug based on DP-107. Previous circular dichroism studies have established that DP-107 is a coiled-coil dimer at micromolar concentrations. In the work proposed here, NMR will be used to fully characterize the tertiary structure of the dimer. A variety of heteronuclear NMR spectra of 13C/15N labeled peptide will be collected. The data from these experiments will be used to compile a detailed list of constraints for distance geometry and molecular dynamics refinement of the solution structure of DP-107. Further structural studies will be aimed at determining the structure of a weakly-associating tetramer. Amino acid side chains directly involved in viral inhibition will be identified by systematic alanine substitutions at each residue. Those with altered biological activity will be studied by NMR to determine the structural perturbations. This data will lead to a map of the structural elements of DP-107 relevant for drug design.